Tertiary- amino-l-aryl-l



Patented Aug. 26, 1952 TERTIARY-AMINO-l-ARYL-l- 4-QUINOLYL) ALKANES ANDPREPARATION THEREOF Alexander R. Surrey, Albany, and Royal A. Cutler,

Troy, N. Y., assignors to Sterling Drug Inc., Wilmington, Del., acorporation of Delaware No Drawing. Original application May 28, 1948,Serial No. 29,936. Divided and this application November 18, 1950,Serial No. 196,522 7 20 Claims (01. 260-286) This invention relates toquinolinecompounds and to processes of preparing the same.

More particularly, this invention relates to basic alpha-aryl-alpha (4quinolyl) alkanenitriles, to derivatives thereof, to addition salts ofsaid compounds, and to processes of preparing the hereinbefore namedcompounds.

Our invention comprehends compounds of the formula where B is a loweraliphatic tertiary-amino radical; X'is a lower alkylene radical; Y is amember of the group consisting of CN, CONI-Iz, and H; A is an arylradical; and Q is a i-quinolyl radical. These compounds are of interestas pharmaceutical agents and as intermediates in preparingpharmaceutical agents.

In'the above formula, the lower aliphatic tertiary-aminoradical,designated as B, comprehends'lower dialkylamino radicals illustrated byexamples such as dimethylamino, diethylamino, ethylmethylamino,di-n-butylamino, and the like; and lower saturated N-heterocyclicradicals illustrated by examples such as l-piperidyl, 4-morpholinyl,3-methyl-l-piperidyl, 2-methyl-l-pyrrolidyl, 2,6-dimethyl-l-piperidyl,and the like. In other words, BH designates a lower aliphaticsecondary-amine as illustrated by diethylamine, di-n-butylamine,morpholine, 3-ethylpiperidine, and the like. The lower alkylene radical,designated as X, includes radicals such as CH2CH:-,

and the like. X further includes alkylene radicals interrupted byelements such as oxygen and sulfur, e. g. --CI-I2CH2OCH2CH3,

Thus, the expression a lower aliphatic tertiaryaminoalkyl radical whenused hereafter in the specification or in the appended claims,comprehends those groups designated as BX-, where B and Xhave themeanings hereinabove described. The aryl radical, designated as A, isone of preferably 6-10 carbon atoms. The aryl radical can be substitutedby such groups as hydroxyl; alkoxyl such asmethoxyl, ethoxyl, etc.;

2 dialkylamino such as dimethylamino; halogen such as chloro, brom'o, oriodo; lower alkyl such as methyl, ethyl, butyl, etc.; and other groupswhich the chemist appreciates will be unafiected by the reactionconditions used in the preparation of the basic compounds of ourinvention.

It is to be understood that the term a 4- quinolyl radical (designatedas Q) as used in this specification and in the appended claims isgeneric, and includes 4- quinolyl radicals wherein the quinoline nucleusmay be substituted by one or more of such groups as: halo, includingchloro, bromo, iodo, and fiuoro; lower alkyl, including methyl, ethyl,propyl, amyl, and the like; hydroxy; lower alkoxy, including methoxy,ethoxy, propoxy, and the like; aryloxy, such as phenoxy; aralkoxy, suchas benzyloxy; trihaloalkyl, such as trifluoromethyl; nitro; amino,substituted-amino, such as acetylamino, ethylamino, dimethylamino,benzylamino, and the like; and other substituents.

As illustrative of our invention the following specific compounds arepresented:

(l) 6 diethylamino-2 (4-methoxyphenyl) -2- (fi-methoxy-i-quinolyl)hexanenitrile,

(2) 4 -dimethylamino ,2 (3-methylphenyll- 2- (3-methyl-8-ethoxy4-quino1yl) pentanenitrile,

3 (3) -(1-piperidyD-2-phenyl 2 (3 bromo- 'Z-chloro -4-quinolyl)-pentanamide,

(5) 3 (4-morpholiny1) 1 phenyl 1 (3,6,7- trimethyl-4-quinolyl) -propane.

one-0H1 o 'N-cmcm kfl OHr-CHa (6) 4 (Z-methyl-l-pyrrolidyl) 1 -qphenyl l-(7-phenoxy-4-quinolyl) -butane,

In addition, our invention comprehends processes for preparing the abovecompounds. These processes are presented in the following chart, whereinB, X, A, and Q have the meanings hereinabove specified, and Z stands forhalogen:

Chart 1 Step (1) of Chart'I involves the condensation of a4-haloquinoline :(I) with a tertiary-amino- 4 2-aryla1kanenitrile (II)in the presence of a strong base to yield a basic nitrile (III). Forexample, 4-diethylamino-2-phenyl-2-('7-chlor0-4- .quinolyl)butanenitrile is prepared .by ,condensing 4,7-dich1oroquinoline with4-diethylamino-2- phenylbutanenitrile in the presence of sodium amide.Other basic condensing agents, e. g. potassium amide, sodium hydride,phenyllithium, and the like, can be used in place of sodium amide.

The intermediate tertiary-amino-2-aryla1kane- .nitriles (II) are agenerally known group of compounds,.which are prepared by condensing inthe presence of'a basic agent, such as sodium amide, a lower aliphatictertiary-aminoalkyl halide, B X halogen. with an arylacetonitrile,ACHzCN, where B, X, and A have the meanings hereinabove specified. Forexample, the preparation of 4-diethy1amino-2-phenylbutanenitrile from2-diethylaminoethyl chloride and phenylacetonitrile is described byEisleb, Ber. 74, 1441 (1941). Other examples are afforded by Kwartlerand Lucas (J. A.'C. 5.68, 2395 (1946)) who describe the preparations of:4-diethylamino-2- (4-chlorophenyl)butanenitrile from 2-diethy1aminoethylchloride and -4-chlorophenylacetonitrile 4-diethylamino-2-(3,4-dichlorophenyl) butanenitrile from 2-diethylaminoethyl chloride and3,4-dichlorophenylacetonitrile; '4-diethylamino-2- (4-methoxyphenyl)butanenitrile from 2- diethylaminoethyl chloride and4-methoxyphenylacetonitrile; 4-dimethylamino-2-phenylbutanenitrile from2-dimethylaminoethyl chloride and phenylacetonitrile; and5-diethylamino-2-(4- .chlorophenyl)-pentanenitrile from3-diethylaminopropyl chloride and 4-chlorophenylacetonitrile.

The intermediate 4-ha1oquino1ines- (1) also are generally well known tothose versed in the-art; ,for representative literature references see:vSurrey et al., J. Am. Chem. Soc. 68, 113, l-244 ,and 2570 (1946); Stecket-al.; ibid..129, 132, 380, and 1241 (1946) Riegel et al.,-ibid. 1229Baker et-ah; ibid. 1267; Mosher et al., ibid. 69, 303 (1947),; Bachmanet al., ibid.'365; Snyder et al., ibid. 371.; and IClintonet al., ibid.704. Some -haloquinolinesthat are useful intermediates inthe-preparationof the'compounds of ourlinvention are listed as follows:

7 3,4-dichloroquino1ine 3A,'5-trichloroquinoline3,+'l=;7-trichloroquinoline =3 bromo-4-chloroquinoline 'B bromo4,7-dich1 lQquinoline V 3-methyl-4-chloro-7 iodoquino1ine3-methy1-4-chloro+8-iodoquinoline 3-methyl-4,5-dichloroquinoline3-methyl-4,7-dichloroquinoline I 3-methyl-4-chloro-'Fbromoquinoliner3-methy1-4-chloro-6-bromoquinolinej3-.methyl-4-chloro-6-ethoxyquinoline 3,6-dimethyl--chloroquinoline-3-methyl-4,8-dichloroquinoline '6emethyl-4-chloro-8-methoxyquino1ine3,8dimethyl-4-chloroquinoline 4;7-dichloroquinoline4-chloro-7-bromoquinoline ous methods.

4,'l-dichloro-ti methoxyquinoline 4,5 -dichloroquinoline3-nitro-4-chloroquinoline 3-amino-4-chloroquinoline4-chloro-7-fluoroquinoline 4-chloro-'7-trifiuoromethylquinoline4,7-dichloro-S-methoxyquinoline 4-chloro-7-phenoxyquinoline3,4-dibromoquinoline 4-chloro-6-nitroquinoline Step (2) of Chart I canbe carried out by vari- In our hands the best results are obtained whena concentrated sulfuric acid solution of the basic nitrile, III, isallowed tostand at room temperature for an extended period. Thus, yieldsof 90% or better of 4-diethylamino- 2-phenyl-2- ('I-chloro-4-quinolyl)butanamide are obtained by allowing the sulfuric acid solution of thecorresponding nitrile to stand at room temperature for about five'weeks. The hydrolysis of the nitrile to the amide, step (2), also canbe performed, but in lower yields, by refluxing the appropriate nitrilewith sodium hydroxide in aqueous ethanol (about 70%) for about twelvehours or with aqueous sulfuric acid (about 60%) for one hour.

Step (3) of Chart I, the complete hydrolysis of the nitrile group to thecarboxyl group which spontaneously loses carbon dioxide, is effected byrefluxing an aqeuous sulfuric acid (about 60%) solution of the nitrile,III, for twelve hours or longer to give practically quantitative yieldsof thebasic quinoline derivative designated as V in Chart I. Forexample, in such a manner 3-diethylamino-1-phenyl-1-('l-chloro-4-quinolyl)propane is prepared from4-diethylamino-2-phenyl-2-('l-chloro-4 quinolyl) butane nitrile.

Step (4) of Chart I, the conversion of the carboxamides designated as IVto the related basic quinoline derivatives designated as V is.

citric acid, benzoic acid and the like; and among the esters of stronginorganic acids and organic sulfonic acids are those such asmethyliodide, ethyl bromide, n-propyl bromide, methyl sulfate,

benzyl chloride, -methyl para-toluenesulfonate,

and the like;

The following examples will illustrate specific embodiments of theinvention.

EXAMPLES v I; Tertiary-amino2-arylalkanenitriles The intermediatetertiary-amino-2-arylalikanenitriles, designated as II in Chart I above,are prepared in excellent yield by condensing a lower aliphatictertiary-aminoalkyl halide with an arylacetonitrile, employing Eislebsprofceclure (Ber. 74, 1441 (1941)) with slightmodifications.Illustrative of this method is the following condensation: of 13-dimethylamino-2- propyl' chloride withphenylacetcnitrile to yieldSodamide (65 g.) is added to a well stirred.

ice-cooled solution of 200 g. (1.7 mole) of phenylacetonitrile in 500ml. of dry benzene. The temperature rises to about 40 C. as the sodiumsalt forms. After stirring for one hour, 180 g. (1.2 mole) ofB-dimethylamino-Z-propyl chloride is added at a rate sufficient to keepthe temperature at 30-35 C. while employing strong external cooling.Stirring is continued for four hours and then water added cautiously.The basic products are extracted from the benzene layer with 2 Nhydrochloric acid, liberated with sodium hydroxide solution, andextracted with ether. After drying the ether solution over anhydrouscalcium sulfate, the ether is removed by distillation and the remainingmaterial is distilled in vacuo, the main fraction, .a colorless oil,distilling at 109-111 C. at 0.8 mm., n :1.5046. This oil (89%) is amixture of 4-dimethylamino- 2-phenylpentanenitrile and 4-dimethy1amino-3-methyl-2-phenylbutanenitrile. The mixture is used as such insubsequent condensations with 4-haloquinolines.

When Z-diethylaminoethyl chloride or 2-dimethylaminoethyl chloride issubstituted for 3- dimethylamino-Z-propyl chloride in the foregoingprocess, about 90% yields of 4-diethylamino- 2-phenylbutanenitrile, B.P. 123 C. at 0.7 mm., n :1.5008, and 4-dimethylamino-2-phenyl-.butanenitrile, B. P. 104-106 C. at 0.5 mm,

11 215055 are respectively obtained. Other tertiary-aminoalkyl chloridesthat are useful in the above procedure include the following: 4-dimethylaminobutyl chloride, 2 di n-butylaminoethyl chloride,3-(1-piperidyl)propyl chloride, 2-(4-morpholinyl)ethyl chloride, 2-(2-methyl-l-piperidyl) ethyl chloride, 3-(1-pyrrolidyDpropyl chloride,2-(2,6-di'methyl- 1- piperidyl) ethyl chloride, 3-(3-methyl-1-piperidyl)propyl chloride, and the like. When used in the above mannerthese lower aliphatic tertiary-aminoalkyl chlorides result in formationof the corresponding tertiary-amino-2- phenylalkanenitriles.

When the foregoing procedure is carried out using, in place ofphenylacetonitrile, a substituted-phenylacetonitrile, the correspondingtertiary amino 2 (substituted phenyDacetonitrile results. For example,the condensation of 4 chlorophenylacetonitrile, 3,4dichlorophenylacetonitrile, or 4 methoxyphenylacetonitrile with2-diethylaminoethyl chloride results in the formation of thecorresponding 4-diethylamino 2 (substituted phenyl) butanenitriles (seeKwartler and Lucas, J. A. C. S. 68, 2395 (1946), who describe theseintermediate nitriles as well as5-diethylamino-2-(i-chlorophenyDpentanenitrile which also can. be usedas an intermediate in our invention).

II. Tertiary-amino-Z-aryZ-Z- (4-quinolyl) alkanenitriles These basicnitriles are prepared by condensing a 4-haloquinoline with atertiary-amino-Z-arylalkanenitrile as described in section I in thepresence of a strong base. In practicing our invention, we prefer touse, as the strong base,

sodium amide, which is readily available, low

costing, and easy to handle. However, other strong bases, such aspotassium amide, sodium hydride, phenyl lithium, and the. like areusable in this process. The following general procedure gives excellentresults: I

mo ma 7 .1T029. dryibenzene. (750. ml)? solution oftthe 4- haloquinoline(0.5 mole) and a tertiary-amino-Z- .arylalkanenitrile (0.5:mole) inaZJ-liter, 3-necked fiask-ifitted with a.stirr'er,.thermometer,andzdrying tube is added 28 g..of fresh, powderedsodium amide. Externa-lcooling 'is applied when necessary-to keep the temperature of the.reaction mixture below 45 C. At the end of about: two to three hours,the temperature drops to ro'om.tem:- perature and stirring is continuedfor an. additional'iour to five hours. Water isa'dded cautiously, themixture shaken vigorously; and the benzenelayer separated, washed withwater, dried over anhydrous calcium sulfate and filtered withdecolorizing charcoal. Removal oi. thebenzene by distillation leaves apractically quantitative yield of the-basic product. Where the bases areobtained as viscous oils, crystallization is induced bystirring-theoilwith a-little ether. Recrystallizationfrom petroleum etheryieldspuresamples of thetertia-ry amino 2'-aryl-2-(4-quinolyl)alkanenitriles as white-crystalline solids. Itis important, in the abovereaction; that the sodium amide be reasonably fresh. When sodium amidethat had been stored forlong periods of time (about six months) is used,the reaction fails to go to completion even after twenty-four hours.

In" orderto remove any unreacted starting materials; a modification ofthe above procedure is employed; The benzene layer, after washingwi'thfour volumes of warm isopropanol. and adding slightly less than thecalculated amount of ethanolic hydrogen chloride. In. some instancesether, is added to turbidity and the solution scratchedto...inducecrystallization. The hydro.- chlorides are dried at 120?invacuo.

Some basic nitrilesprepared in the above manner. are. those having theformula CeHs.

and having the melting'points given in Table I:

' Table I I M. P. Hy R R Z Base drochloride (cm) o. (corn) H GHQ; 72%ears-233:8 -01 v CH'3- 115.5-116 274. and 4- 7-61 on; 1058-1014 264.4-266;

H. ch 731 75 2164217 e01 02m 123 2424.8 243.5-245 I .7-Cl c2115. 91.8-93. .4 21 2-218. 6

"Appears to exist in' two crystalline. modification's. Wien firstl33lit31 it'. chisel ates- 1019 C.

Y When. theioregoing; procedure is employed using as thereactants;ldiethylamino-z @i-chloro- V 8 phenyhbutaiienitrile; and;4.7-dich1oroquino1m, the resulting product is 4-diethylamin'o-2.- (4-chlorophenyl) 2 (7. chlorox-efiquinolyD- butanenitrile, M. P.1Q8;.9.'-.1.10.6- .(corr).

Strong basic condensing agents, other than sodium amide .canbe' usedtoprepare the-tertiaryamino-2-aryl-2- (4quinolyl).alkanenitriles. of ourinvention. For example, we .foundphenyllithium and sodium hydride to beeffective, however, the resultant yields of desired basic nitrile-are.considerably less. than when sodium amide is used. Examples. using thesetwo. condensing agents follow: V V

Phenyllithium is prepared. under. nitrogen by the action. of.l.53 g.(0.22 mole) of lithium .metal on. 11.3:g. (0.1 mole) of chlorobenzeneinether, according to standard procedures (Gilmanet'al, J .'A. C. S. 55.1252 (1933) and Method for Preparationi of; Organo Lithium Compounds]?13am.- phlet, CX- SE Form 10, Lithaloys Corp i4 1: Madison Ave;,New-York 22, N. Y). However, it is to :be. noted thattthere is aconsiderable amount .of lithiumwhich. fails to-react because of a-blackcoating; that forms on the surface of the metal. After removal of: theunreacted lithium with tweezers, a solution of 21 g.. (0.1.mole)ore-diethylamino-2-phenylbutanenitrile in 50 ml. of ether is.added,;therebeing a'heat of reaction that "causes: the ether to reflux.The resultin solution is then stirred for fiveminutes andi 19.8. g.((1.1. mole) of 4,7i. dichloroquinoline added. .The brightred mixture isrefluxed for one andonehalfhours, and thenworked up, according to theabove: general :procedure using: sodium amide: as the condensing.agentto give-21.27% yield of very pure. product,e=diethylamino-2phenyi2e( 1- chloro-4"-quinolyl)butanenitrile. Twelvegrams of 4,7-dichloroquinoline is recovered unchanged, which is probablydue to the low conversion of lithium to phenyllithium;

Equimolecular. amounts of: 4-diethylamin'ox-2- phenylbutanenitrile,4,7-dichloroquinoline', and a slightexcess of' sodium: hydride in. drybenzene are-z refluxed-for sixteen hours; After: working up according tothe previously described procedure using sodium .amide as the condensingagentga 27% yield of. 4-diethylamino-2ephenyl- 2'- (7-chloro-4-quinolyl)butanenitrile; is obtained. Note that the sodium hydride used inthis:run was the last: ofa bottle which had stood. for some time;Possible deterioration: of. theasodium hydride may account. for thelowyield; 'i

Iinaddition, the following tertiary-aminot-Z-'aryl-2-(4-quinolylT-aikanenitriles are formed using the above generalprocedure by condensing the appropriatetertiary-amino-2-arylalkanenttrile' with the appropriate l-ha'loquinolinef 4- di'ethylamino-Z (4 '-methoxyphenyl) 2 (6- methoxy -equinol'yl) butanenitrile, 5'-- diethylamino '2" (4* chlorophenyl) 2"(GB-dichloro -4-quinolyl) pentanenitrile, 4- (e' morpholinyll 2-(Bytdichloroplienyl) ---2=- (3 nitro- 4-quinolyl)butanenitrila and4-(2-methyl-l piperidyl) 2 phenyl .2 (3 methyl 7- iodo-4-quinolyl)butanenitrile;

When-the. aboveprocedure. i carried out" using for the.tertiary-amino-2-arylalkanenitrile the mixture of"4-dimethylamino-2-phei1ylpentanenit'rile and'4-dimethyIamino-B-methyLzphenylbutanenitrile- (the mixture. beingobtained by the condensation. of. 3-dimethylamino 2 propyl chloride andphenylacetonitrile according to directions giveninExample I), amixtu reof co nd nsation products is. obtained, For. example, co d tion 1; 99s,("0.94.- mole); ofg-dimethyl- 9 amino-2-phenylalkanenitrile (the abovereferred to mixture) and 185 g. (0.94 mole) of 4,7-dichloroquinolineusing sodium amide, according to the general directions given above,yields 330 g. (0.91 mole) of viscous oil, from which three whitecrystalline solids are separated. The oil is warmed and poured slowlyinto 1.5 liters of rapidly stirred ether. After stirring for, threehours, the light tan solid which separates is filtered off; yield is 115g., M. P. 138-160 C. (fraction A). Trituratlon of the crude solid fortwenty minutes with boiling petroleum ether (B. P. 60-68 C.) yields 46g. of product, M. P. 165-169 C. Two recrystallizations from 600 ml.portions of absolute ethanol yields 32 g. of white rhombic plates, M. P.182-l83.8 C. (corn), the structure of which is discussed below.

The ether filtrate, after the removal of fraction A, is treated withexcess ethanolic hydrogen chloride and the ether decanted from the oilwhich separates. added to the oil, and the mixture refluxed andtriturated to give a yellow-orange solid which is collected byfiltration (fraction B). The solid is dissolved in water, filtered withcharcoal, and the free base liberated from the filtrate by means ofsodium bicarbonate solution. The base is taken up in ether, the ethersolution dried, filtered with charcoal, and evaporated. The remainingoil is dissolved in 200 ml. of benzene and allowed to stand for fivehours. The solid that separates (35 g., M. P. l46-l49 C.) is dissolvedin 350 ml. of absolute ethanol and the solution filtered hot withcharcoal. On cooling, 22 g. of white prismatic crystals separates; M. P.15l-152 C. (corn). (A mixed melting point with a sample isolated fromfraction A is 136-143" 0.). The structure of this compound is discussedbelow.

The acetone filtrate, after the removal of traction B, is evaporated,the resulting oil dissolved in water, the free base liberated with Twoliters of acetone are.

10, they have either Formula VIII or IX:

H; oHmN'cHomc-oN N VIII Gel-I5 oHomomoH o-orr III.Tertiary-amiho-Z-aryZ-Z-(4-quinolyl) alkanamides:

These basic amides are prepared by partially hydrolyzing thecorresponding basic nitriles dealkali solution and taken up in a largevolume of ether. After drying of the ether solution, the ether isremoved by distillation to give an oil which is slurried with a smallvolume of fresh ether to give 9 g. of a white solid, M. P. 135-140 C.(fraction C). The product is heated with 175 ml. of petroleum ether.(B.P. 60-68 C.) and the mixture filtered while hot. On cooling, thefiltrate yields 3 g. of pale yellow solid which is recrystallized, withcharcoaling, from petroleum ether to give 2 g. of whiteprisms, M. P.142-144 C., which has the same empirical formula as the compoundsisolated from fractions A or B. A mixed melting point with either ofthese compounds isolated from fractions A or B is depressed.

Since the abovethree compounds isolated from fractions A, B, and C wereprepared by condensing 4,7-dichloroquinoline with a mixture of 4-dimethylamino Z-phenylpentanenitrile (VI) and4-dimethylamino-3-methyl-2-phenylbutanenitril (VII),

CaHt

(CHOzNCH CHaCHCN Chm (ormmomcnenon' H: VII

scribed in section II. The following general procedure gives excellentresults:

A solution of one part by weight of a tertiaryamino-2-aryl-2-(l-quinolyl)alkanenitrile as described in section II in four volumes ofconcentrated sulfuric acid is allowed to stand at'room temperature forfour to five weeks. The yellow solution is poured onto ice, treated withan excess of sodium hydroxide solution, and extracted with chloroform.The extract is dried over anhydrous calcium sulfate, filtered withcharcoal, and the chloroform removed by distillation to leave the crudeamide in yields of or better. Recrystallization from benzene or tolueneyields, as

a white crystalline solid, a tertiary-amino-2 -aryl-Y above manner arethose having the formula 00H: RomomoHr-b-oomr,

and having the melting points given in Table i With decomposition.

Exists in a lower melting elevated form, M. P. 90-92" 0., whenrecrystallized from benzene.

In addition, the following tertiary-amino-2- aryl-2-(4-quinolyl)-alkana1 nides are formed by partially hydrolyzing the correspondingbasic nitriles: A=diethylamino=2e (eemethoxyphenyl) 2-(firmethoxyelequinolyl) ebutanamlde, 541i? ethylamino 2 (4 chlorophenyl) 2 2' (6,8dichloro 4 r quinolyl) :1 pentana-mide, {l r (#1 r morpholinyl) 2 .(3,4dichlorophenyl) 2 (3 nitro 4 quinolyl) butanamide, and i (2 methyl 1piperidyl) 2 .phenyl 2 (3 methyl .-"7 iodo 4 9 quinolyDbutanamide. -'rhepartial hydrolysis of the basic nitriles to the corresponding basicamides can be effected by other reaction conditions. For example, when 4diethylamino 2 phenyl 2 (7 chloro 4-quinolyl)butanenitrile is allowed tostand for 12 and-the ether: extract dried, filtered with char coal andevaporated to give a pale yellow oil. In some instances a; small amountof intermediate basicamide (described in Example'III) is isol'ated evenafter a reflux period of 48 hours. This is removed by dissolving the oilin petroleum ether (B. P. 60- 68' CJ, seeding with the amide, andallowing the mixture to: stand for 24 hours. Evaporation of the filteredsolution yields the de: sired -tertiary-aminol-l-aryl l (4 quinolyl)al.- kane, which can be converted into the hydrochloride without furtherpurification .or distilled in vacuo to give pale yellow tinted oils.

. The mono-hydrochlorides are prepared by dis-.- solving the free basein three volumes of isopropanol and adding slightly less than theequiv.- alent amount of alcoholic hydrogen chloride." In order to inducecrystallization, ether is added to turbidity, the inside of the i'laskscratched, and the solution allowed to; stand. In some preparationsseveral days passbefore crystallization occurs.

Some basic com-pounds prepared in the above manner are those having theformula N and ha ing the ph sical ccn tant i e n Table 111-:

Table III' Be M-Ro l P-PQ- eg ster 6 a -elat- 2005 201.; (corn) 1;

. $1 196.6-19725 (corr. ;taken s o ly) IV. -Trtiary-amino-1-dryl-1(4equinol yl) alk cmes These basic compounds are obtained from thecorresponding basic nitriles as described in sec-- tion II by completehydrolysis of the nitrile group to the carboxylgroup which spontaneouslyloses carbon dioxide. 'Ighe following general procedure gives excellentresults:

A solution of 30 g. of a tertiary-amino-2-aryl- 2-(4-quinoly1)alkanenitrile in 50 m1. of water and 50 ml. of concentratedsuliuric acidis refluxed for 12 to 48 hours. The completeness of the reaction can bedetermined by passing nitrogen over the surface of the reaction mixtureand bubbling the escaping gases through barium hydroxide solution. nocloudiness results after a minute or so, the reaction is regarded ascomplete. lhe reaction mixture is poured onto ice containing" an excesso-f sodium hydroxide solution, the liberated base extracted with ether,

In addit o t e fol ow ng teary-enmiry -l-( -guino1y1 alkan s a e i imethe bo e. e eral procedure o ompletely hy rol z 1948,v no 1 5- Pat n.2,::570;Z8.-6 issued Qctobe 9, 1951, which claims thetertiary-amino-2-aryl= 2- (4-quinolyl) alkanenitriles illustrated inExample II hereinabove. The tertiary-amino-Z-aryl- 2-(4-quinolyl)alkanamides, which are illustrated in Example III above, are disclosedand claimed in our copending application Serial Number H 196,521, filedNovember 18,1950.

We claim: 1. A compound selected from the group consistmg of basiccompounds having the formula where B isa lower aliphatic terti ry-ammoradif cal, X is a lower alkylerie radical, A is an aryl radical of thebenzene series, and Q is e. l-ou'inolyl radical, and acid addition saltsthereof 2. A compound selected from the group consisting ofB-dimethylamino-l phenyl-l-(i quinr olyDpropane and acid addition saltsthereof 3. A compound selected from the group consisting of3-dimethylamino-l-phenyl-l- (5-chloro-4- quinolyl) propane and acidaddition salts thereof.

4. A compound selected from the group consisting of -3'-dimethylamino-l-phenyl-l- ('l-chloro-4- quinolyhpropane and acid addition saltsthereof.

5. A compound selected from the group consisting of 3-diethylaminol-phenyl-le(5chloro-4-' quinolyl) propane and acid addition saltsthereof.

6. Acompound selected from the groupconsisting of3-diethylamino-l-phenyl-l-('l-chloro-4- quinolyDpropane and acidadditionsalts thereof.

'7. A process of preparing a compound having the formula i i r where Bis a lower aliphatic tertiary-amino radical, X is alower alkyleneradical, "A is an aryl radical of the benzene series and Q is a4-quin0lyl radical, whichcomprises reacting a 4-haloquinoline of theformula Q-halogen with a basic alphaarylalkanenitrile of the formula inthe presence of a strong base to yield a basicalpha-aryl-alpha-(4-quinolyl)a1kanenitrile of the formula Q andsubjecting said basic alpha-aryl-alpha-(iquinolyl) alkanenitrile tovigorous treatment with strong mineral acid whereby said nitrile ishydrolyzed to the corresponding acid with simultaneous loss of carbondioxide by refluxing it with aqueous sulfuric acid for about twelve tofortyeight hours.

8. A process for preparing a compound having the formula where B is alower aliphatic tertiary-amino radical, X is a lower alkylene radical, Ais an aryl 14" radical of the benzene series and Q is a 4-quinolylradical, which comprises hydrolyzing the related carboxamide of theformula i BX(}"JOONH2 Q to the corresponding carboxylic acid withsimultaneous loss of carbon dioxide by refluxing it with aqueoussulfuric acid for about twelve to fortyeight hours. i g

10. A compound havingthe formula V CgHs (lower alkyllzN- XC-H where X isa lower. alkylene radical and Q is the. 7-chloro-4-quinolyl radical.

11. A compound having the formula V C5115 (lower alkyl);N-X +H where Xis a loweralkylene radical-and Q is the 5-.chloro-4-quinoly1 radical. Yi

12 A compound having the formula ea. (lower allsyl);NX- (3-41 where X isa lower alkylene radical and. Q is the 4-quinolyl radical.

13. A process for preparing a compound having the formula CtHs (lowerallryl);N--X l-H where X is a lower alkylene radical and Q is theI-chloro-i-quinolyl radical, which comprises completely hydrolyzing therelated nitrile of the formula CeHs (lower alkylhN-X-C-CN to thecorresponding carboxylic acid with simultaneous loss of carbon dioxideby refluxing it with aqueous sulfuric acid for about twelve tofortyeight hours.

14. A process for preparing a compound having the formula (loweralkyl);NX- 1 H where X is a lower alkylene radical and Q is the5-ch1oro-4-quinolyl radical, which comprises completely hydrolyzing therelated nitrile of the formula CeHs (lower alkyl)il:-T-X+CN to thecorresponding carboxylic acid with simultaneous loss of carbon dioxideby refluxing it with aqueous sulfuricacid for about twelve toforty-eight hours.

lira-process forpreparing-a: compound ha'vihe theroi mula w w (loweralkyl) 3NX-(|-)H n v Q where X is a lower alkylene radical and Q is the-quinolyl radical, which comprises completely hydrolyzin'g the relatednitrile of the formula I Q CaHt (lower alkyI) N-X?CN s Q to thecorresponding carboxylic acid with simultaneous loss of carbon dioxideby refluxing it with aqueous sulfuric acid for'abou't'twelve tofortyeight hours.

16. A process for preparing 3-dimethylamino- I-phen'yI-I (4-quinolyl)propane which comprises completely hydrolyzing" 4 dimethylamino 2phenyl-2-(4-quinolyl)butanenitrile tothe corresponding carbo-xylic acidwith simultaneous loss of carbon dioxide by refluxing it with aqueoussulfuric acid for about twelve to forty-eight hours.

17. A process for preparing 3-dimethylamino1-phenyl-I-(5-chloro-4-quinolyl')propane which comprises completelyhydrolyzing' 4-dimethyl-- amino-2-phenyl-2-(5chloro-4-quinoly1)butanenitrile to the corresponding carboxylic acidwith simultaneous:losszoricarhomdioxideby'refluxineit with; aqueoussulfuric aoid' for about twelve to, fdrty-eighthours 18. A process; for:preparingg 3.-dimethylamino- 1-phenyle1r(7-chloro-4-qu1nolyl)propane:-which comprises completely hydrolyzing 4-diinethyl amino-'2-phenyl-2s (7chloro-i-quinolyl)butanenit'rile to the; corresponding carboxylic acidwith simultaneous lossiof; carbon di'oxidaby' refluxing it withaqueous;sulfuric acid forabout twelve toforty-eight hours;

19. A process for; preparmg; 3-diethylam1no-1'- plienyl- 1Z- (5-chlorof4::- :quin'olyl) propane which comprises completelyhydrolyzing;4--diethy1- aminoP-ZV-phenyI-Z- (5 -:ehloro'-4-quinoly1)ibutanernitri'leto the; corresponding; carboxylio acid-with simultaneous:lossrof carbon dioxide-1 by refluxing it withaque'o'us' sulfuric acid:forabout-twelve-to" forty eight'hours.

20. A- process; for preparing 3-diethylamino l-phenyl-l- (7-chloro-4-quinolyl) propane; which; comprises completely hydrolyzing 4diethylamino-2-phenyl-2- (7 chloro- 4-quino1y1) butanenitrile to thecorresponding carboxylic acid with simultaneous loss of carbon dioxideby refluxing itlwith-aqueous-sulfuric acid for about twelvetoforty-eight hours. 7

V ALEXANDER-R; SURREY.

ROYAL A. CUTLER.

Noreferencescited.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BASIC COMPOUNDHAVING THE FORMULA